Pge3 esters and alkanoates

ABSTRACT

1. A COMPOUND OF THE FORMULA:   1-(O=),2-(R3-OOC-(CH2)3-CH=CH-CH2-),3-(CH3-(CH2)4-   CH(-O-R2)-CH=CH-),4-(R2-O-)CYCLOPENTANE   WHEREIN R3 IS HYDROCARBYL OF ONE TO 13 CARBON ATOMS, INCLUSIVE, AND R2 IS HYDROGEN OR LOWER ALKANOYL.

United States Patent Oifice 3,839,409 Patented Oct. 1, 1974 3,839,409PGE ESTERS AND ALKANOATES Sune Bergstrom and Jan Sjovall, both ofKemiska Institutionen Karolinska Institutet, Stockholm, Sweden NoDrawing. Application Aug. 23, 1972, Ser. No. 283,045, which is acontinuation of abandoned application Ser. No. 115,113, Feb. 12, 1971,which is a continuation-inpart of application Ser. No. 203,752, June 20,1962, now'Patent No. 3,598,858, which is a continuation-inpart ofabandoned application Ser. No. 199,209, Apr. 9, 1962, which in turn is acontinuation-in-part of application Ser. No. 738,514, May 28, 1958, nowPatent No. 3,069,322. Divided and this application June 6,

1973, Ser. No. 367,678 5 Claims priority, application Great Britain,Mar. 29, 1962, 62/ 12,139 Int. Cl. C07c 61/36, 69/74, 69/28 US. Cl.260-468 D 8 Claims I ABSTRACT OF THE DISCLOSURE Alkanoates andhydrocarbyl esters of the prostaglandins PGE and PGE, are disclosed.These novel compounds are useful for a'variety of pharmacologicalpurposes, including use as smooth muscle stimulants and ascardiovascular agents.

CROSS REFERENCE TO RELATED APPLICATIONS DESCRIPTION OF THE INVENTIONThis invention relates to novel compositions of matter. One aspect ofthis invention is specifically concerned with novel organic compounds ofthe formula: I

OR: I

wherein R is hydrocarbyl of 2 to 13 carbon atoms, inclusive, and R ishydrogen or lower alkanoyl.

Another aspect of this invention is specifically con cerned with novelorganic compounds of the formula:

wherein R is hydrocarbyl of one to 13 carbon atoms, in-

- elusive, and R is hydrogen or lower alkanoyl.

Another aspect of this invention is specifically concerned with novelorganic compounds of the formula:

I C OOCHa wherein R is 'alkanoyl of 3 to 8 carbon atoms, inclusive.

Another aspect of this invention is specifically concerned with novelorganic compounds of the formula:

238, 3555 (1963), Bergstrom et al., Pharmacol. Rev.

20, 1 (1968), and references cited in those.

In formulas I, II, III, and IV, a broken line attachment to thecyclopentane ring indicates a chain or group in alpha configuration,i.e., below the plane of the cyclopentane ring. A heavy solid lineattachment to the cyclopentane ring indicates 'a chain in betaconfiguration, i.e., above the plane of the cyclopentane ring. Theconfiguration of the side chain hydroxy in formulas I, H, III, and IV isS.

vThese compounds of formulas I, II, III, and -IV are all variouslyesters, alkanoates, and ester-alkanoates of the prostaglandinsdesignated now as PGE and PGE3, previously designated bisdehydro-PGE andtetradehydro- PGE. See our said copending application Ser. No. 203,752.

The structural formulas of PGE (V) and PGE (VI) are as follows:

A systematic name for PGE is 7 [3a hydroxy 2B- [(35) 3hydroxy-trans-l-octenyl]-5-oXo-lu-cyclopentyl]-cis-5-heptenoic acid. Asystematic name for PGE is 7 [3mhydroxy-ZB-[(3S)-3-hydroxy-trans-1,cis-S-octadienyl] 5oxo-la-cyclopentyl]-cis-5-heptenoic acid.

With regard to formula I, examples of hydrocarbyl of 2 to 13 carbonatoms, inclusive, are alkyl, e.g., ethyl, propyl, hexyl, decyl;cycloalkyl, e.g., cyclopropyl, 2-butylcyclopropyl, cyclobutyl,cyclobutylmethyl, 3 -pentylcyclobutyl, 2,2-dimethylcyclobutyl,cyclopentyl, 3-tertbutylcyclopentyl, 2-cyclopentylethyl, cyclohexyl,cyclohexylmethyl; aralkyl, e.g., benzyl, phenethyl, l-phenylethyl, 2-phenylpropyl, 3-phenylbutyl, 2-(l-naphthylethyl), benzhydryl; aryl,e.g., phenyl, p-tolyl, p-ethylphenyl, p-tertbutylphenyl, l-naphthyl; andsuch unsaturated moieties as allyl, crotyl, and propargyl.

With regard to formula II, examples of hydrocarbyl of one to 13 carbonatoms, inclusive, are those mentioned above and also methyl.

With regard to formula III, examples of alkanoyl of 3 to 8 carbon atoms,inclusive, are propionyl, butyryl, valeryl, hexanoyl, heptanoyl,octanoyl, and branched chain isomeric forms of those, e.g., isobutyryland isovaleryl.

With regard to formulas I, II, and IV examples of lower alkanoyl arealkanoyl of 2 to 8 carbon atoms, inclusive, e.g., those mentioned aboveand also acetyl.

The novel esters and alkanoates of formulas I, II, III, and IV areextremely potent in causing stimulation of smooth muscle as shown, forexample by tests on strips of guinea pig ileum, rabbit duodenum, orgerbil colon. These compounds are also highly active in potentiatingother known smooth muscle stimulators, for example, oxytocic agents,e.g., oxytocin and the various ergot alkaloids including derivatives andanalogs thereof. Accordingly, these novel formulas I, II, and IIIcompounds are useful in place of or in combination with less than theusual amount of these and other known smooth muscle stimulators wheneversmooth muscle stimulation is needed to alleviate or prevent somephysiological condition in mammals, including humans, useful domesticanimals, pets, zoological specimens, and laboratory animals, forexample, mice, rabbits, rats, and monkeys. For example, these compoundscan be used to alleviate or prevent conditions of gastrointestinal atonyin mammals, including humans, e.g., paralytic ileus following anesthesiaand surgical operation or from other medical causes. For this purpose,the compound is administered parenterally, e.g., subcutaneously,intramuscularly or by intravenous injection or infusion in a dose range0.1 to 2 mg. per kg. of body weight per day, the exact dose depending onthe age, weight, and condition of the patient or animals, and thefrequency and route of administration. Small repeated doses areindicated when the aim is to prevent rather than alleviate the atony.

Another smooth muscle stimulatory area where these novel formula I, II,III, and IV compounds are useful, is in the control of prevention ofatomic uterine bleeding in mammals after abortion or delivery, to aid inthe expulsion of the placenta, and during the puerperium. For thispurpose, the compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.1to about 100 g. per kg. of body Weight per minute until the desiredeffect is obtained. Subsequent doses are given by intravenous,subcutaneous, or intramuscular injection or infusion during puerperiumin the range 0.1 to 2 mg. per kg. of body weight per day, again theexact dose depending on the age, weight, and condition of the patient oranimal.

In still another smooth muscle stimulatory area, these novel compoundsof formulas I, II, III, and IV are surprisingly useful in place ofoxytocin to induce labor in pregnant female animals, including man,cows, sheep, and pigs, at or near term, or in pregnant animals withintrauterine death of the fetus from about weeks to term. For thispurpose, the compound is infused intravaneously at a dose of 0.1 to g.per kg. of body weight per minute until at or near the termination ofthe second stage of labor, i.e., expulsion of the fetus. These compoundsare especially useful when the female is one or more weeks post-matureand natural labor has not started, or 12 to 60 hours after the membraneshave ruptured and natural labor has not yet started. An alternativeroute of administration is oral.

The novel compounds of formulas I, II, III, and IV are also surprisinglyuseful for controlling the reproductive cycle in ovulating femalemammals, including humans and animals such as monkeys, rats, rabbits,dogs, cattle, and the like. By the term ovulating female mammals ismeant animals which are mature enough to ovulate but not so old thatregular ovulation has ceased. For that purpose, dihydro-PGE for example,is administered systemically at a dose level in the range 0.1 mg. toabout 20 mg. per kg. of body Weight of the female mammal, advantageouslyduring a span of time starting approximately at the time of ovulationand ending approximately at the time of menses or just prior to menses.Intravaginal and intrauterine are alternative routes of administration.Additionally, expulsion of an embryo or a fetus is accomplished bysimilar administration of the compound during the first third of thenormal mammalian gestation period.

The novel compounds of formulas I, II, III, and IV are also useful inmammals, including man, as nasal decongestants. For this purpose, thecompounds are used in a dose range of about 10 g. to about 10 mg. perml. of a pharmacologically suitable liquid vehicle or as an aerosolspray, both for topical application.

The novel compounds of formulas I, II, III, and IV are useful inmammals, including man and useful animals, e.g., dogs and pigs, toreduce and control excessive gastric secretion, thereby reducing oravoiding gastrointestinal ulcer formation, and accelerating the healingof such ulcers already present in the gastrointestinal tract. For thispurpose, the compounds are injected or infused intravenously,subcutaneously, or intramuscularly in an infusion dose range about 1 g.to about 100 g. per kg. of body Weight per minute, or in a total dailydose by injection or infusion in the range about one to about 50 mg. perkg. of body weight per day, the exact dose depending upon the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The novel formula I, II, III, and IV compounds lower systemic arterialblood pressure in anesthetized (pentobarbital sodium)pentolinium-treated rats with indwelling aortic and right heartcannulas. Accordingly, these novel compounds are useful as hypotensiveagents to reduce blood pressure in mammals, including man. For thispurpose, the compounds are administered by intravenous infusion at therate about 0.1 to about 100 g. per kg. of body weight per minute, or insingle or multiple doses of about 100 g. to 5 mg. per kg. of body weighttotal per day.

The novel compounds of formulas I, II, III, and IV are potentantagonists of epinephrine-induced mobilization of free fatty acids asshown, for example, by inhibition of the spontaneous release of glyeeralfrom isolated fat pads. For this reason, these compounds are useful inexperimental medicine for both in vitro and in vivo studies in mammals,including man, rabbits, and rats, intended to lead to the understanding,prevention, symptom alleviation, and cure of diseases involving abnormallipid mobilization and high free fatty acid levels, e.g., diabetesmellitus, vascular diseases, and hyperthyroidism.

The novel formula I, II, III, and IV compounds of this invention areused for the purposes described above in ester form (I, II, and III), inester-alkanoate form (I, II, and III), and in alkanoate form (IV) eitheras the free acid or in pharmacologically acceptable salt form.

With regard to the ester forms of I and II, those can be any esterswithin the above definitions of R or R However, it is preferred that theR or R moiety not contain olefinic or acetylenic unsaturation. Morepreferred are alkyl esters wherein the alkyl moiety contains two to 8carbon atoms, inclusive (1), or one to 8 carbon atoms, inclusive (II).Especially preferred are alkyl of two to 4 carbon atoms, inclusive (I),or one to 4 carbon atoms, inclusive (II). Of those alkyl, methyl (II)and ethyl (I) are especially preferred for optimum absorption of thecompound by the body or experimental animal system.

Examples of alkyl of one to 4 carbon atoms are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkylof one to 8 carbon atoms are those mentioned above, and also pentyl,hexyl, heptyl, octyl, and branched chain isomers thereof, e.g.,2-ethylhexyl.

With regard to the alkanoate of ester-alkanoate forms of I, II, III, andIV, the alkanoyl moiety is any of those within the definition of R R andR However, acetyl is especially preferred for optimum absorption of thecompound by the body or experimental animal system. In formulas I andII, it is intended that both R be hydrogen or that both be alkanoyl.

Pharmacologically acceptable salts of formula IV useful for the purposesdescribed above are those with pharmacologically acceptable metalcations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium and potassium, and from the alkaline earthmetals, e.g., magnesium and calcium, although cationic forms of othermetals, e.g., aluminum, Zinc, and iron, are within the scope of thisinvention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triiso propylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, tit-phenylethylamine, [3 phenylethylamine,ethylenediamine, diethylenetriarnine, and like aliphatic,cycloaliphatic, and araliphatic amines containing up to and includingabout 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine,morpholine, pyrrolidine, piperazine, and loweralkyl derivatives thereof,e.g., l-methyl piperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,Z-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolami-ne, 2-amino-1-butanol,2-amino-2-ethyl-1,3-propanediol, 2-arnino-2 methyl 1- propanol,tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N (p tertamylphenyl)diethanolamine, glactamine, N-methylglucamine,N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine,and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

When the novel formula I, II, III, and IV compounds are used forintravenous injection or infusion, sterile aqueous isotonic solutionsare preferred. For subcutaneous or intramuscular injection, sterilesolutions or suspensions of the compound in aqueous or non-aqueous mediaare used. Tablets, capsules, and liquid preparations such as syrups,elixers, and simple solutions, with the usual pharmaceutical carriers,are used for oral or sublingual administration. For rectal, vaginal, orintrauterine administration, suppositories, lavage and douchepreparations, and solutions as such or contained in a sponge, all

prepared by methods known in the art, are used.

The novel esters of formula I wherein R is hydrogen are prepared byesterification of the carboxylic acid known as PGE (formula V). Thenovel esters of formula 6 II wherein R is hydrogen are prepared byesterification of the carboxylic acid known as PGE (formula VI). Thepreparation of these reactant acids PGE and PGE is described in our saidcopending application Serial No. 203,752.

The novel dialkanoates of formula III are prepared by carboxyacylatingthe methyl ester of PGE That methyl ester is prepared as described belowby esterification of PGE The novel dialkanoates of formula IV areprepared by carboxyacylating PGE (Z is --CH CH or by carboxyacylatingPGE (Z is cis-CH=CH--).

When an ester-alkanoate of formula I or II is desired, that ispreferably prepared by carboxyacylation of the corresponding esterrather than by esterification 'of the corresponding dialkanoate.

The esterification of PGE and PGE to produce the hydroxy esters offormulas I and II (all R =H) is accomplished by procedures known in theart. These reactants PGE and PGE are sensive to acid and base, andneutral esterification conditions are preferred. Illustratively, thealkyl esters of formulas I and II are prepared by reaction of the acid,PGE or PGE with the appropriate diazohydrocarbon. For example, whendiazomethane is used, the methyl esters are produced. Similar use ofdiazoethane, diazobutane, and 1-diazo-2-ethylhexane, for example, givesthe ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablydiethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be nolonger than necessary to effect the desired esterification, preferablyabout one to about ten minutes, to avoid undesired molecular changes.Diazohydrocarbons are known in the art or can be prepared by methodsknown in the art. See, for example, Organic Reactions, I ohn Wiley &Sons, Inc., New York, N.Y., Vol. 8, pp. 839-394 (1954).

An alternative method for esterification of the carboxyl moiety of PGEor PGE comprises transformation of the free acid to the correspondingsilver salt, followed by interaction of that salt with an alkyl iodide.Examples of suitable iodides are methyl iodide, ethyl iodide, butyliodide, isobutyl iodide, tert-butyl iodide, and the like. The silversalts are prepared by conventional methods, for example, by dissolvingthe acid in cold dilute aqueous ammonia, evaporating the excess ammoniaat reduced pressure, and then adding the stoichiometric amount of silvernitrate.

By reacting diazomethane with PGE as above described, the necessaryester reactant for the compounds of formula III is prepared.

The ester-dialkanoates of formulas I, II, and III, and the dialkanoatesof formula IV are prepared by reacting the corresponding dihydroxycompounds with the appropriate alkanoic anhydride, i.e., correspondingto analkanoic acid of 2 to 8 carbon atoms, inclusive in the case offormulas I, II, and IV, and corresponding to an alkanoic acid of 3 to 8carbon atoms in the case of formula HI. Examples of these anhydrides areacetic anhydride, propionic anhydride, butyric anhydride, valericanhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride,and isomeric forms of those.

This reaction leading to these dialkanoates is advantageously carriedout by mixing the hydroxy compound and the acid anhydride, preferably inthe presence of a tertiary amine such as puridine or triethylamine. Asubstantial excess of the anhydride is used, preferably about 10 to10,000 moles of anhydride per mole of the hydroxy compound reactant. Theexcess anhydride serves as a reaction diluent and solvent. An inertorganic diluent, for example, dioxane, can also be added. It ispreferred to use enough of the tertiary amine to neutralize thecarboxylic acid produced by the reaction, as well as any free carboxylgroups present in the hydroxy compound reactant.

The reaction is preferably carried out in the range about to about 100C. The necessary reaction time will depend on such factors as thereaction temperature, and the nature of the anhydride and tertiary aminereactants. With acetic anhydride, pyridine, and a C. reactiontemperature, a 12 to 24-hour reaction time is used.

The desired dialkanoate is isolated from the reaction mixture byconventional methods. For example, the excess anhydride is decomposedwith water, and the resulting mixture acidified and then extracted witha solvent such as diethyl ether. The desired dialkanoate is recoveredfrom the diethyl ether extract by evaporation. The

dialkanoate is then purified by conventional methods,

advantageously by chromatography.

The novel formula IV free acids are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. In the case of the inorganic salts, itis usually suitable to dissolve the acid in water containing thestoichiometric amount of a hydroxide, carbonate, or bicarbonatecorresponding to the inorganic salt desired. For example, such use ofsodium hydroxide, sodium carbonate, or sodium bicarbonate gives asolution of the sodium salt of the prostanoic acid derivative.Evaporation of the water or addition of a water-miscible solvent ofmoderate polarity, for example, a lower alkanol or a lower alkanone,gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent ofeither moderate or low polarity. Examples of the former are ethanol,acetone, and ethyl acetate. Examples of the latter are diethyl ether andbenzene. At least a stoichiometric amount of the amine corresponding tothe desired cation is then added to that solution. If the resulting saltdoes not precipitate, it is usually obtained in solid form by additionof a miscible diluent of low polarity or by evaporation. If the amine isrelatively volatile, any excess can easily be removed by evaporation. Itis preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid with the stoichiometric amount of the corresponding quaternaryammonium hydroxide in water solution, followed by evaporation of thewater.

The invention can be more fully understood by the following examples.

Example 1: PGE methyl ester To a dry ether solution of one milligram(2.8 micromoles) of PGE is added a Slight excess of diazomethane,prepared in ether from four micromoles of nitrosomethylurethane. Thereaction mixture is allowed to stand for about five minutes ,and theether and excess diazomethane distilled off. On distillation to dryness,PGE methyl ester is obtained; mass spectral peaks at 346, 328, 315, 297,277, 259, and 188 mass spectral units.

Example 2: PGE ethyl ester An ethereal solution of diazoethane isprepared by mixing 1.5 g. of N-ethyl-N-nitrosourea, 20 ml. of diethylether, and 4 ml. of aqueous potassium hydroxide solution. The diethylether solution is decanted from the aqueous layer and is added dropwiseto a solution of PGE; (300 mg.) in ml. of ethanol until a yellow colorremains. The mixture is then stirred for 15 minutes at 25 C. Evaporationunder reduced pressure then gives PGE ethyl ester.

Following the procedure of Example 2, PGE is esterified to PGE ethylester.

Following the procedures of Examples 1 or 2 but replacing thediazomethane or the diazoethane with diazobutane, l-diazo 2 ethylhexane,cyclohexyldiazomethane, and phenyldiazomethane, and using in turn PGEand PGE there are obtained in butyl, 2-ethylhexyl, cyclohexylmethyl, andbenzyl esters of PGE and PGE Example 3: PGE methyl ester diacetate PGEmethyl ester (10 mg.) is mixed with acetic anhydride (2 ml.) andpyridine (2 ml.). The resulting mixture is allowed to stand at 25 C. for18 hours. The reaction mixture is then cooled externally with ice,diluted with water, and then acidified with dilute hydrochloric acid topH 1. That mixture is extracted three times with diethyl ether. Thecombined extracts are washed successively with dilute hydrochloric acid,dilute aqueous sodium bicarbonate solution, and water, dried, andevaporated to give PGE methyl ester triacetate.

Following the procedure of Example 3 but using propionic anhydride,isobutyric anhydride, and hexanoic anhydride each in place aceticanhydride, and using each in turn, PGE PGE and the methyl, ethyl, butyl,2-ethylhexyl, cyclohexylmethyl, and benzyl esters of PGE and PGE thereare obtained the dipropionates, diisobutyrates, and dihexanoates ofthese PGE and PGE acids and esters.

Also following the procedure of Example 3 but replacing PGE methyl esterwith PGE ethyl ester, there is obtained PGE ethyl ester diacetate.

We claim:

1. A compound of the formula:

wherein R is hydrocarbyl of one to 13 carbon atoms, inelusive, and R ishydrogen or lower alkanoyl.

2. A compound according to claim 1 wherein R is alkyl of one to 8 carbonatoms, inclusive, and both R are hydrogen.

3. A compound according to claim 1 wherein R is methyl and both R arehydrogen.

4. A compound according to claim 1 wherein R is alkyl of one to 8 carbonatoms, inclusive, and both R; are lower alkanoyl.

5. A compound according to claim 1 wherein R is alkyl of one to 8 carbonatoms, inclusive, and both R are acetyl.

6. A compound according to claim 1 wherein R is methyl and both R areacetyl.

9 10 7. A compound of the formula: 8. A compound according to claim 7wherein both R are acetyl. E References Cited /W Samuelssm, J.A.C.S. 85,1878 (1963).

COOH 5 Axen et a1., Chem. Comm. 602 (1970).

ROBERT GERSTL, Primary Examiner R50" H oRfi U.S. Cl. X.R.

260-211 R, 247.2 R, 268 R, 243.65, 326.3, 410, 429.9,

wherein both R are lower alkanoyl, and pharmacologi- 439 R, 448 R, 488R, 50M SOLIS, 50117, 5012 514D cally acceptable salts thereof.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTIONPATENT NO. 3, 59, 9 DATED October 1, 1974 INVENTOR(S) Sune Bergstrom etal It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 5, l ine 57, "control of prevent ion" shou ld read control orprevention Column 6, l ine 20, "sens i ve" should read sensitive Column8, line 14, "obtained in butyl" should read obtained the butyl lines48-55, that part of the formula reading V\ Should read H -0R H Signedand Scaled this Thirteenth D y f September 1977 [SEAL] A ttest:

RUTH C. MASON LUTRELLE F. PARKER Attesting Officer Acting Commissionerof Patents and Trademarks

1. A COMPOUND OF THE FORMULA: